PROJECT 3: MITOCHONDRIAL FUNCTION AND VISION AGING - SUMMARY/ABSTRACT Progressive decline of visual function with age increases the susceptibility to social isolation and falls. It also leads to inactivity, which contributes to skeletal muscle weakness and wasting. The physiology of age-related visual impairment is not well understood, and there is no effective treatment. We have found that spatial visual function in C57BL/6 mice declines ~60% between 24 and 34 months, independent of optical changes in the eye, which is accompanied by mitochondrial abnormalities in photoreceptors, and disc pathology in outer segments. We have also found that feeding a high fat diet (HFD) to young mice leads to a more rapid decline of visual function, which was accompanied by mitochondrial abnormalities in the retinal pigment epithelium (RPE) and choroidal vasculature. We hypothesized that impaired retinal mitochondrial energetics was the cause of age- and HFD-related visual decline. In support of this, we have found that the topical administration of the mito-protective peptide (SS-31) to the eye was able to reverse both age- and HFD-induced visual decline and its associated retinal pathology. Based on these and more recent preliminary results we now hypothesize that (1) age-related mitochondrial dysfunction in photoreceptors leads to visual decline; (2) HFD damages the choroidal vasculature resulting in ischemia-induced mitochondrial dysfunction in the RPE; (3) Dietary excess will exacerbate age-related visual decline; (4) SS-31, by restoring mitochondrial structure and promoting bioenergetics in both photoreceptors and RPE, will ameliorate and even reverse visual decline caused by age and dietary excess; and (5) SS-31 exerts its anti-aging effects by promoting mitochondrial bioenergetics rather than simply scavenging reactive oxygen species (ROS). We will test these hypotheses in three aims: 1) Determine the mechanisms by which SS peptides reverse age- induced visual decline; 2) Determine the mechanisms of any interaction between age and HFD on visual decline, and whether treatment with SS-31 can reverse it; and 3) Establish the visual healthspan and aging benefits of SS-31 as a shared PO1 aim. Experiments will determine the degree to which oxidative stress, and bioenergetics failure, contribute to age- and HFD-related visual decline. They will also will evaluate a) cellular and mitochondrial structural changes in photoreceptors and RPE; b) changes in choroidal blood flow; c) mitochondrial function and oxidative stress in retina slices; c) oxidative changes to cytochrome c and electron transfer characteristics (with Core D); d) protein biomarkers for retinal blood flow, bioenergetics, oxidative stress, and inflammation; e) proteomic analyses of retinas (with Core C); and f) metabolomics for measuring redox state of retinas (with Core E). Finally, as part of a shared P01 aim to establish the translational benefits of SS-31, we will determine visual performance longitudinally over the mouse lifespan after SS-31 is continuously delivered from middle age to mice fed standard and high fat diets.